Clinical Update on Uses for Mifepristone in Obstetrics and Gynecology.

Importance: Mifepristone (RU-486) is a selective progesterone receptor modulator that has antagonist properties on the uterus and cervix. Mifepristone is an effective abortifacient, prompting limitations on its use in many countries. Mifepristone has many uses outside of induced abortion, but these are less well known and underutilized by clinicians because of challenges in accessing and prescribing this medication. Objectives: To provide clinicians with a history of the development of mifepristone and mechanism of action and safety profile, as well as detail current research on uses of mifepristone in both obstetrics and gynecology. Evidence Acquisition: A PubMed search of mifepristone and gynecologic and obstetric conditions was conducted between January 2018 and December 2021. Other resources were also searched, including guidelines from the American College of Obstetricians and Gynecologists and the Society of Family Planning. Results: Mifepristone is approved by the Food and Drug Administration for first-trimester medication abortion but has other off-label uses in both obstetrics and gynecology. Obstetric uses that have been investigated include management of early pregnancy loss, intrauterine fetal demise, treatment of ectopic pregnancy, and labor induction. Gynecologic uses that have been investigated include contraception, treatment of abnormal uterine bleeding, and as an adjunct in treatment of gynecologic cancers. Conclusions and Relevance: Mifepristone is a safe and effective medication both for its approved use in first-trimester medication abortion and other off-label uses. Because of its primary use as an abortifacient, mifepristone is underutilized by clinicians. Providers should consider mifepristone for other indications as clinically appropriate.

Glucocorticoid receptor blockers.

Mifepristone is the only glucocorticoid receptor antagonist currently approved for the treatment of Cushing's syndrome. Although originally developed as an abortifacient due to its blockade of the progesterone receptor, a number of case reports documented its efficacy as a glucocorticoid receptor blocker going back to 1985. The SEISMIC trial, published in 2012, provided sufficient data on efficacy and adverse effects for regulatory approval. Mifepristone provides clear benefits on glycemia, blood pressure, muscle weakness, body weight and the other myriad clinical manifestations of Cushing's syndrome. However, because it blocks the glucocorticoid receptor, blood cortisol and ACTH levels actually rise, rather than fall; this complicates patient management. Doses are adjusted based on clinical manifestations rather than hormone levels. Adverse effects include adrenal insufficiency due to overdosage, hypokalemia, and menorrhagia. Treatment of severe adrenal insufficiency requires high doses of dexamethasone. Other glucocorticoid receptor blockers without effects on the progesterone receptor are being developed. Because mifepristone inhibits CYP3A and CYP2C8/2C9, drug-drug interactions can occur. These potential adverse effects can largely be avoided with careful attention to detail. My opinion is that its current place in therapy is in patients with severe disease and in those not responding to other treatments.

Similarities and differences between embryonic implantation and CTC invasion: Exploring the roles of abortifacients in cancer metastasis chemoprevention.

Mifepristone (RU486) is a chemical contraceptive marketed in more than 55 countries and used by hundreds of millions of women worldwide. Current studies reported its uses by both genders for a safe and long-term psychotic depression and particularly for traditional cancer chemotherapy. Here, we investigated the multidisciplinary data from recent large epidemiological chemoprevention studies for long-term use of oral contraceptives to reduce cancer risk, and from the unsuccessful clinical trials of mifepristone used as a post-metastatic anticancer drug, and elucidated the similarities and differences in cellular and molecular processes between embryonic implantation to endometrium and adhesion/invasion of circulating tumor cells (CTCs) to vascular endothelium. The deep analyses provide a stronger scientific basis for repurposing abortifacients for safe and effective cancer metastatic chemoprevention. Initiation of such cancer drug development strategy represents a paradigm shift from traditional post-metastasis treatments to novel pre-metastasis chemoprevention.

Management of 14 patients with cornual heterotopic pregnancy following embryo transfer: experience from the past decade.

OBJECTIVE: There are two major management approach for cornual heterotopic pregnancy, transvaginal cornual embryo reduction with ultrasound guidance, or laparoscopic cornual resection. This no consensus on the optimal management for cornual heterotopic pregnancy. Here, we are trying to determine the optimal management approach for patients with viable cornual heterotopic pregnancy following embryo transfer. METHODS: This is a retrospective cohort study conducted at the locally largest reproductive center of a tertiary hospital. A total of 14 women diagnosed as viable cornual heterotopic pregnancy following embryo transfer. Six patients were treated with cornual pregnancy reduction under transvaginal ultrasound guidance without the use of feticide drug (treatment 1), and eight patients were treated with laparoscopic cornual pregnancy resection (treatment 2). RESULTS: All 14 patients of cornual heterotopic pregnancy following embryo transfer due to fallopian tubal factor, among which, 12 patients had cornual pregnancy occurred in the ipsilateral uterine horn of tubal pathological conditions. Nine (64.29%) showed a history of ectopic pregnancy. Thirteen (92.86%) patients were transferred with two embryos and only one patient had single embryo transferred. Six patients received treatment 1, and 2 (33.33%) had uterine horn rupture and massive bleeding which required emergency laparoscopic surgery for homostasis. No cornual rupture occurred among patients received treatment 2. Each treatment group had one case of spontaneous miscarriage. The remaining 5 cases in treatment 1 group and the remaining 7 cases in treatment 2 group delivered healthy live offspring. CONCLUSION: Patients with tubal factors attempting for embryo transfer, especially those aiming for multiple embryos transfer, should be informed with risk of cornual heterotopic pregnancy and the subsequent cornual rupture. Compared with cornual pregnancy reduction under transvaginal ultrasound guidance, laparoscopic cornual resection might be a favorable approach for patients with viable cornual heterotopic pregnancy.

Post Abortion Care and Management After Induced Abortion During the COVID-19 Pandemic: A Chinese Expert Consensus.

The rapid spread of novel coronavirus (COVID-19) has posed complex challenges to global public health. During this pandemic period, access to essential services including post-abortion care (PAC) has been disrupted. Along with the clinical management of the disease in women, protection of the healthcare workers and medical staff from nosocomial infection is important to ensure infection control. Thus, in order to implement the proper contraceptive measures and to reduce the rate of repeated abortion, the family planning group of minimally invasive gynecological branch of the Liaoning Medical Association organized a committee of experts to formulate guidance and suggestions to ensure the timely treatment and surgery of women opting for abortion, the implementation of PAC, implementation of safe contraceptive measures after surgery, and the protection of healthcare professionals and medical staff from infection. We believe these guidelines might be helpful for obstetrics and gynecology departments in China and globally, as well for women who wish to undergo abortion during these unprecedented times.

Effect of oral misoprostol, alone or in combination with aglepristone, on mid-term pregnancy termination in cats.

OBJECTIVES: This study aimed to determine the efficacy and safety of oral misoprostol (MIS) administration in the induction of mid-term pregnancy termination in cats. METHODS: Twenty-eight cats that were pregnant for 30-40 days were allocated to four groups. The aglepristone (AGL) group (n = 7) received 10 mg/kg SC aglepristone q24h for two consecutive days. In the AGL+MIS group (n = 7), AGL (as administered in the AGL group) and MIS (200 µg/cat PO q12h until the start of abortion) were administered. The MIS200 (n = 7) and MIS400 groups (n = 7) received MIS (200 or 400 µg/cat misoprostol, respectively) alone PO q12h until the start of abortion. Blood samples were collected at the start of treatment (d0), 4 days after the start of treatment (d4) and on the day of complete abortion/end of administration (dA/d7). RESULTS: The efficacy of the treatment was 71.4% in the AGL group, 100% in the AGL+MIS group, 0% in MIS200 group and 57.4% in MIS400 group (P = 0.004). No significance was found in relation to the interval from treatment to the start/end of abortion and the duration of abortion in all groups. The most observed side effect was vomiting in both groups administered MIS, particularly in the MIS400 group (56.7%). Progesterone (P4) concentrations were reduced during the abortion, but not to basal levels, in all groups. P4 concentrations were significantly lower at dA/d7 in the MIS400 group compared with the AGL and AGL+MIS groups (P = 0.002). CONCLUSIONS AND RELEVANCE: The results obtained from this study showed that low doses of MIS do not induce abortions in cats but increase the effect of AGL. Although higher doses could terminate pregnancies, this also causes intense unwanted side effects. Therefore, the use of MIS alone as an abortifacient in cats is not recommended. For mid-term pregnancy termination in cats, the combination of misoprostol and aglepristone provides a more effective abortifacient than using either of them alone.

Complications related to induced abortion: a combined retrospective and longitudinal follow-up study.

BACKGROUND: Induced abortion is one of the most common gynecological procedures in Sweden, but there is still little knowledge about the adverse effects. The aims of this study are to provide an overview of complications of medical and surgical abortions and to evaluate the impact of bacterial screening to prevent postabortal infections. METHODS: All women who underwent induced abortion at Skaraborg Hospital between 2008 and 2015 are included in the study. Bacterial screening for chlamydia, gonorrhea, mycoplasma, and bacterial vaginosis was performed prior to the abortions. Abortion complications, categorized as bleeding, infection, or incomplete abortion were assessed in women who came in contact with the gynecological clinic within 30 days after the procedure. RESULTS: A total of 4945 induced abortions were performed during the study period. Nearly all, 4945 (99.7%) were eligible for inclusion in the study. Medical abortions < 12 weeks were the most common procedure (74.7%), followed by surgical abortions (17.5%), and medical abortion > 12 weeks (7.8%). Complications were registered in 333 (6.7%) of all abortions. Among medical abortions < 12 weeks, the complication frequency increased significantly, from 4.2% in 2008 to 8.2% in 2015 (RR 1.49, 95% 1.04-2.15). An incomplete abortion was the most common complication related to medical abortions < 12 weeks. Of all women who tested positive for one or several bacteria at the screening and therefore received antibiotics, 1.4% developed a postabortal infection. Among those who tested negative at the screening, 1.7% developed infectious complications. CONCLUSIONS: The share of complications related to medical abortions < 12 weeks increased significantly during 2008-2015 without any evident cause. Women who tested positive for one or several bacteria upon screening and received antibiotics experienced almost an equal proportion of postabortal infections compared to women who tested negative upon screening. The screening process seems to fulfill its purpose of reducing the risk of infectious complications.

Evidence-based management of non-tubal ectopic pregnancies.

Recent advances in ultrasonography and the use of other modalities including magnetic resonance imaging scans have led to the early and more accurate diagnosis of non-tubal ectopic pregnancies (NTE). As a result, the management of these pregnancies has evolved. This article addresses the management options currently available for NTE. While surgical management remains the mainstay of treatment for ovarian, abdominal and cornual ectopics, there is growing evidence that some of these can be managed medically. Many authors have utilised a combination of medical and surgical approaches in the management of cervical and caesarean section (CS) scar ectopic pregnancies with good outcome. The availability of dedicated early pregnancy units has further improved diagnosis and more importantly the follow-up care for these patients. The rarity of cases and the difficulty of ethically organising randomised trials for NTE remain a problem in formulating consistent pathways for optimum management of women with NTE.

Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention.

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (

Virus Zika y aborto por correspondencia, una realidad cercana a Chile / Zika virus and correspondence abortion, a reality close to Chile

Ante las evidencias de causalidad entre la infección prenatal de virus ZIKA y el desarrollo de microcefalia y otras anomalías cerebrales fetales, publicadas en el año 2016, en Latinoamérica ha surgido mucha incertidumbre sobre el acceso al aborto en mujeres embarazadas infectadas por el virus. Pese a que existe diversidad regulatoria en la región, hoy existen diferentes instancias que facilitan el aborto farmacológico a las mujeres, incluso en países donde está prohibido. Sin embargo esta realidad no se centra exclusivamente en el brote de virus ZIKA, sino que este hecho ha dejado en evidencia la forma como ONG's internacionales ingresan y facilitan el acceso del aborto farmacológico en diferentes países. Este escenario surgiere la interrogante de cómo enfrenta Chile el desarrollo de esta realidad, ante lo cual se muestra la incidencia de la ONG Women on Web en Chile luego de la alerta epidemiológica emitida por la OPS en noviembre de 2015 por virus ZIKA. Desde Chile se presentaron 442 peticiones de aborto farmacológico en 107 días después de emitida la alerta. Estos datos revelan que en Chile, pese a no estar afectado por virus ZIKA, de hecho se usan las plataformas web que proveen de un "aborto farmacológico por correspondencia". Esta evidencia muestra como hoy en Chile existe acceso al aborto farmacológico, tanto desde ONG's internacionales como la presentada, pero también en el comercio informal, todo promovido desde los alcances de las tecnologías de comunicación.

In lieu of the evidence of causality between prenatal ZIKA virus infection and the development of microcephaly and other fetal cerebral anomalies, published in 2016, there has been a surge of uncertainty in Latin America over the access to abortion in pregnant women infected by the virus. Even though diverse regulation exists in the region, today there are many different instances that facilitate women's to pharmacological abortion, even in countries where it is prohibited. However, this reality doesn't center exclusively in the ZIKA virus outbreak, rather this event has emphasized how international NGOs enter and facilitate access to pharmacological abortion in different countries. This scenario suggests the question of how Chile confronts the development of this reality, in which the marked incidence of the NGO Women on Web is shown in Chile after de epidemiology alert emitted by the PAHO in November of 2015 because of the ZIKA virus. Chile presented 442 petitions for pharmacological abortion in the 107 days following the alert notification. This data reveals that Chile, although unaffected by the ZIKA virus, has use of web platforms that provide a "pharmacological abortion by correspondence". This evidence demonstrates how access to pharmacological abortion exists today in Chile, not only from international NGO like the one mentioned, but even through informal commerce, promoted by the reach of communication technology.

Treatment Decisions at the Time of Miscarriage Diagnosis.

OBJECTIVE: To describe the factors patients and physicians prioritize during first-trimester miscarriage management and assess what drives satisfaction with care. METHODS: We conducted a mixed-methods study of clinically stable women seeking surgical, medical, or expectant miscarriage treatment. Women with first-trimester fetal demise or anembryonic gestation (N=55) completed demographic and psychosocial surveys. Using purposive sampling, 45 (82%) completed in-depth interviews. Fifteen obstetricians were interviewed. Participants described factors that informed their counseling (physicians) or decision-making (patients). Content analysis used an integrated approach with inductively and deductively derived codes. Patient-derived themes were stratified by treatment choice. Associations between variables and treatment choices were analyzed. RESULTS: Thirty-four women (62%) received surgical management, 19 (35%) received medical, and two (4%) received expectant. Physicians expected that women with prior pregnancies have strong management preferences, and indeed, multigravid patients were less likely to change their initial treatment choice after counseling than primigravid patients (12% compared with 42%, odds ratio [OR] 0.18, 95% confidence interval [CI] 0.04-0.81, P=.03). Physicians favored patient-centered decisions and patients chose the treatment that they thought would least affect other responsibilities. Those ultimately receiving surgical management had a higher monthly income (adjusted OR 1.30, 95% CI 1.04-1.63, P=.023) and more social support (adjusted OR 2.45, 95% CI 1.07-5.61, P=.035) than the medical group. The surgical group cited loss acceptance, a favorable perception of surgery, and a desire to expedite the miscarriage as decisive factors. The medical group endorsed control over, and timed completion of, the miscarriage in a more intimate setting, an aversion to surgery or anesthesia, and a perception of improved fertility preservation as decisive factors. Regardless of treatment choice, satisfaction with treatment was linked to a supportive clinical team and expeditious resolution. CONCLUSION: Prior pregnancy experiences, obligations, and sociodemographic factors influence miscarriage management decision-making. Structured counseling, especially for primigravid patients, could improve both the physician and the patient experience with miscarriage care.

Use of Medicinal Plants with Teratogenic and Abortive Effects by PregnantWomen in a City in Northeastern Brazil / Uso de Plantas Medicinais com Efeitos Teratogênicos e Abortivos por Gestantes em uma Cidade no Nordeste do Brasil

Purpose The purpose of this study is to verify the use ofmedicinal plants by pregnant women treated at four Basic Health Units and at a public maternity facility in Brazil s northeast. Methods This is a cross-sectional, quantitative study, performed between February and April 2014. The subjects were 178 pregnant women, aged 18 to 42 years. To collect data, a structured questionnaire with dichotomous and multiple choice questions was used. To verify the correlation between the variables, Pearson s chi-square test was used. Results The study showed that 30.9% of the pregnant women used medicinal plants, and boldo was the most cited (35.4%). All the plants utilized, except lemongrass, have toxic effects in pregnancy, according to Resolution SES/RJ N° 1757. There was no statistically significant correlation between social class and use of medicinal plants. Conclusion The health of the study participants and their unborn children is at risk due to the inappropriate use of medicinal plants.

Objetivo Verificar o perfil de uso de plantas medicinais por gestantes atendidas em quatro Unidades Básicas de Saúde da Família e em uma maternidade pública da cidade de Campina Grande - PB, na região Nordeste do Brasil. Métodos Estudo transversal, quantitativo, desenvolvido no período de Fevereiro a Abril de 2014. Foi incluída uma amostra com 178 gestantes com idade entre 18 e 42 anos. O instrumento de coleta foi um questionário estruturado com perguntas dicotômicas e de múltipla escolha. Para verificar a associação entre as variáveis estudadas, utilizou-se o teste Qui-quadrado de Pearson. Resultados Foi constatado que 30,9% das gestantes utilizavam plantas medicinais, sendo o boldo a mais citada (35,4%). Entre as plantas utilizadas com alta frequência pelas gestantes, todas, com exceção apenas da Erva-Cidreira (Melissa officinalis), apresentavam possíveis efeitos tóxicos para a gestação, segundo a Resolução SES/RJ N° 1757. Ao comparar a classe social e o uso de plantas medicinais, não observou-se relação significante. Conclusões A saúde das grávidas que fazem uso de plantas consideradas medicinais, assim como a de seus filhos, sofrem riscos devido ao uso inadequado destas plantas.

The efficacy of the systemic methotrexate treatment in caesarean scar ectopic pregnancy: A quantitative review of English literature.

To determine the efficacy and safety of primary medical treatment with systemic methotrexate (MTX) in caesarean scar ectopic pregnancy, we conducted a Medline/PubMed search on the relevant English literature from January 1978 to January 2012. The search yielded 27 publications of 40 cases of caesarean scar ectopic pregnancy. The literature search showed a very liberal use of systemic MTX treatment with unfavourable outcomes, although the major determinant of the clinical efficacy was found in here to be ß-hCG level together with embryonic cardiac activity (ECA) status. A caesarean scar ectopic pregnancy presented with a serum ß-hCG concentration of ≤ 12,000 mIU/ml (odds ratio, OR 5.68, 95% confidence interval, CI, 1.37-23.48) and absence of ECA (OR 4.80, 95% CI, 1.14-20.08) was found to be associated with higher efficacy rate of primary systemic MTX treatment. Administration of primary systemic MTX treatment was found to be ideal for a caesarean scar ectopic pregnancy presented before 8 weeks' gestation, with a ß-hCG concentration of ≤ 12,000 mIU/ml together with an absent ECA (OR 14.52, 95% CI, 2.36-89.09).

The association between serum progesterone and outcome of medical management of early fetal demise: a pilot study.

The study objective was to determine the relationship between serum progesterone level and the outcome of mifepristone-misoprostol regimen for medical management of missed miscarriage up to 12 weeks. A blood sample was collected just before mifepristone administration for serum progesterone assay. After 48 h, misoprostol 800 µg was administered vaginally; further 400 µg was administered 4 h later if necessary. Treatment was classed as a success if retained tissues were expelled within 72 h (Group 1), and a failure if this did not occur (Group 2). Of 52 analysed cases, complete medical evacuation occurred within 72 h in 40 (76.9%) women (serum progesterone ranged 13-90 nmol/l). Serum progesterone between the two groups were statistically significant (p < 0.001), by Mann-Whitney test. Of the 12 patients who did not respond, nine (75%) women had serum progesterone < 10 nmol/l. We found mifepristone-misoprostol regimen is less effective in missed miscarriage when serum progesterone is < 10 nmol/l.

Acridine: a versatile heterocyclic nucleus.

Acridine is a heterocyclic nucleus. It plays an important role in various medicines. A number of therapeutic agents are based on acridine nucleus such as quinacrine (antimalarial), acriflavine and proflavine (antiseptics), ethacridine (abortifacient), amsacrine and nitracine (anticancer), and tacrine. Acridine is obtained from high boiling fraction of coal tar. It is also obtained in nature from plant and marine sources. Acridine undergoes a number of reactions such as nucleophilic addition, electrophilic substitution, oxidation, reduction, reductive alkylation and photoalkylation. The present review article summarizes the synthesis, reaction, literature review and pharmaceutical importance of acridine.

Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety.

OBJECTIVE: To discuss the mechanism of action of selective progesterone receptor modulators (SPRMs) and summarize the preclinical and clinical efficacy and safety data supporting the potential use of these compounds for gynecologic indications. DESIGN: Relevant publications from 2005 onward were identified using a PubMed search. Additional relevant articles were identified from citations within these publications. SETTING: None. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): None. RESULT(S): Mifepristone was first developed as a progesterone receptor antagonist and licensed for pregnancy termination because of the unique property of this compound to terminate pregnancy when associated with prostaglandins. Then SPRMs were developed, and among those ulipristal acetate, an efficient emergency contraceptive. Because SPRMs effectively inhibit endometrial proliferation and reduce endometriotic lesions in animal models, this suggests a possible role in the treatment of endometriosis in humans. Finally, a number of double-blind, randomized, placebo-controlled trials have demonstrated the efficacy of asoprisnil, mifepristone, telapristone acetate, and ulipristal acetate in reducing leiomyoma and uterine volume, and suppressing bleeding in women with uterine fibroids. CONCLUSION(S): Mifepristone in combination with prostaglandins has been licensed for pregnancy termination because of its unique ability is this area. Ulipristal acetate is available for emergency contraception. Several SPRMs hold further promise as an effective medical therapy for patients suffering from endometriosis and leiomyoma.

Induction of abortion with aglepristone in cats on day 45 and 46 after mating.

The aim of this study was to test for the efficacy and safety of the use of aglepristone for pregnancy termination on day 45 in cats. Six healthy cats were treated with 10 mg/kg aglepristone sc on day 45 and 46 after mating; six other cats served as untreated controls. The effect of treatment was monitored by general examination, vaginal cytology, ultrasonography and blood sampling for haematology and progesterone determination. Besides, interoestrus interval and next pregnancy including litter size were recorded. The efficacy of treatment was approximately 67% (4/6) with abortion occurring 4-7 days after the first injection and a sanguineous discharge and erythrocytes in vaginal smears for at least 6 days afterwards. The two treated cats that did not abort gave birth to two kittens on day 67 and had a stillbirth of a single kitten on day 71, respectively. As expected enlargement of the mammary glands and lactation were observed in all treated cats. No other treatment-induced side effects were observed. Progesterone levels at abortion were high (30-140 nmol/l), but were decreased on day 55. Aglepristone treatment did not affect fertility in following cycles. Finally, it can be concluded that late-term pregnancy termination with aglepristone is possible but due to a success rate of 67% an ultrasonographical examination 7 days after treatment is an inherent necessity to control the effect of treatment.

Medical or surgical abortion and psychiatric outcomes.

AIM: The objectives of this study are to compare the risk of psychological depression after medical and surgical abortions in first two trimesters and to evaluate the risk factors for post-abortion depression. METHOD: A retrospective study was conducted throughout 367 women who underwent surgical abortion and 458 women who underwent medical abortion between January 2006 and January 2007 in Dr. Zekai Tahir Burak Women's Health Hospital. Women were assessed by clinical psychologists one week after the intervention. The clinical characteristics and psychological assessment of these women were statistically correlated by means of non-parametric tests. RESULTS: Of the study population, 27.1% was diagnosed with post-abortion depression. The frequency of post-abortion depression was 34.3% in surgical abortion patients and 22.8% in medical abortion patients. The women who underwent surgical abortion were found to have significantly elevated risk of post-abortion depression. The women with a high risk of post-abortion depression were significantly younger and had a more frequent history of psychiatric and depressive disorders. CONCLUSION: An important quotient of women experiences post-abortion mood depression which is significantly more frequent after surgical abortion. Women with past psychiatric and anxiety disorders should be carefully monitored for depression when they would undergo an abortion.